Interleukin 1 receptor antagonist knockout mice show enhanced microglial activation and neuronal damage induced by intracerebroventricular infusion of human β-amyloid

Craft, Watterson, Hirsch Emmet, Van

Description

Interleukin 1 (IL-1) is a key mediator of immune responses in health and disease. Although classically the function of IL-1 has been studied in the systemic immune system, research in the past decade has revealed analogous roles in the CNS where the cytokine can contribute to the neuroinflammation and neuropathology seen in a number of neurodegenerative diseases. In Alzheimer's disease (AD), for example, pre-clinical and clinical studies have implicated IL-1 in the progression of a pathologic, glia-mediated pro-inflammatory state in the CNS. The glia-driven neuroinflammation can lead to neuronal damage, which, in turn, stimulates further glia activation, potentially propagating a detrimental cycle that contributes to progression of pathology. A prediction of this neuroinflammation hypothesis is that increased IL-1 signaling in vivo would correlate with increased severity of AD-relevant neuroinflammation and neuronal damage. Methods To test the hypothesis that increased IL-1 signaling predisposes animals to beta-amyloid (Aβ)-induced damage, we used IL-1 receptor antagonist Knock-Out (IL1raKO) and wild-type (WT) littermate mice in a model that involves intracerebroventricular infusion of human oligomeric Aβ1–42. This model mimics many features of AD, including robust neuroinflammation, Aβ plaques, synaptic damage and neuronal loss in the hippocampus. IL1raKO and WT mice were infused with Aβ for 28 days, sacrificed at 42 days, and hippocampal endpoints analyzed. Results IL1raKO mice showed increased vulnerability to Aβ-induced neuropathology relative to their WT counterparts. Specifically, IL1raKO mice exhibited increased mortality, enhanced microglial activation and neuroinflammation, and more pronounced loss of synaptic markers. Interestingly, Aβ-induced astrocyte responses were not significantly different between WT and IL1raKO mice, suggesting that enhanced IL-1 signaling predominately affects microglia. Conclusion Our data are consistent with the neuroinflammation hypothesis whereby increased IL-1 signaling in AD enhances glia activation and leads to an augmented neuroinflammatory process that increases the severity of neuropathologic sequelae.

Sujets

• Alzheimer's disease
• Beta amyloid
• Animal model
• IL1A
• Microglía

Informations

• Publié par: biomed
• Publié le: 01 janvier 2005
• Nombre de lectures: 9
• Langue: English

Extrait

Journal of Neuroinflammation

BioMedCentral

Open Access Research Interleukin 1 receptor antagonist knockout mice show enhanced microglial activation and neuronal damage induced by intracerebroventricular infusion of humanβ-amyloid 1,2 1,34,5 Jeffrey M Craft, D Martin Watterson, Emmet Hirschand Linda J Van 1,2 Eldik*

1 2 Address: Centerfor Drug Discovery and Chemical Biology, Northwestern University, Chicago, IL, USA,Cell and Molecular Biology, 3 Northwestern University Feinberg School of Medicine, Chicago, IL, USA,Molecular Pharmacology and Biological Chemistry, Northwestern 4 University Feinberg School of Medicine, Chicago, IL, USA,Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, 5 Chicago, IL, USA andDepartment of Obstetrics and Gynecology, Evanston Northwestern Healthcare, Evanston, IL, USA Email: Jeffrey M Craft  [e-mail]; D Martin Watterson  m[e-mail]; Emmet Hirsch  e [e-mail]; Linda J Van Eldik*  [e-mail] * Corresponding author

Published: 20 June 2005Received: 24 May 2005 Accepted: 20 June 2005 Journal of Neuroinflammation2005,2:15 doi:10.1186/1742-2094-2-15 This article is available from: http://www.jneuroinflammation.com/content/2/1/15 © 2005 Craft et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Alzheimer's diseaseamyloid betaanimal modelglial activationinterleukin1microglia

Abstract Background:Interleukin 1 (IL-1) is a key mediator of immune responses in health and disease. Although classically the function of IL-1 has been studied in the systemic immune system, research in the past decade has revealed analogous roles in the CNS where the cytokine can contribute to the neuroinflammation and neuropathology seen in a number of neurodegenerative diseases. In Alzheimer's disease (AD), for example, pre-clinical and clinical studies have implicated IL- 1 in the progression of a pathologic, glia-mediated pro-inflammatory state in the CNS. The glia-driven neuroinflammation can lead to neuronal damage, which, in turn, stimulates further glia activation, potentially propagating a detrimental cycle that contributes to progression of pathology. A prediction of this neuroinflammation hypothesis is that increased IL-1 signalingin vivowould correlate with increased severity of AD-relevant neuroinflammation and neuronal damage. Methods:To test the hypothesis that increased IL-1 signaling predisposes animals to beta-amyloid (Aβ)-induced damage, we used IL-1 receptor antagonist Knock-Out (IL1raKO) and wild-type (WT) littermate mice in a model that involves intracerebroventricular infusion of human oligomeric Aβ1–42. This model mimics many features of AD, including robust neuroinflammation, Aβplaques, synaptic damage and neuronal loss in the hippocampus. IL1raKO and WT mice were infused with Aβfor 28 days, sacrificed at 42 days, and hippocampal endpoints analyzed. Results:IL1raKO mice showed increased vulnerability to Aβ-induced neuropathology relative to their WT counterparts. Specifically, IL1raKO mice exhibited increased mortality, enhanced microglial activation and neuroinflammation, and more pronounced loss of synaptic markers. Interestingly, Aβ-induced astrocyte responses were not significantly different between WT and IL1raKO mice, suggesting that enhanced IL-1 signaling predominately affects microglia. Conclusion:Our data are consistent with the neuroinflammation hypothesis whereby increased IL-1 signaling in AD enhances glia activation and leads to an augmented neuroinflammatory process that increases the severity of neuropathologic sequelae.

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